ADVERSE REACTIONS SECTION.

6 ADVERSE REACTIONS The following adverse reactions associated with the use of vasopressin were identified in the literature. Because these reactions are reported voluntarily from population of uncertain size, it is not possible to estimate reliably their frequency or establish causal relationship to drug exposure.Bleeding/lymphatic system disorders: Hemorrhagic shock, decreased platelets, intractable bleedingCardiac disorders: Right heart failure, atrial fibrillation, bradycardia, myocardial ischemiaGastrointestinal disorders: Mesenteric ischemia Hepatobiliary: Increased bilirubin levelsRenal/urinary disorders: Acute renal insufficiencyVascular disorders: Distal limb ischemiaMetabolic: HyponatremiaSkin: Ischemic lesionsPostmarketing ExperienceReversible diabetes insipidus [see Warnings and Precautions (5.2)] The most common adverse reactions include decreased cardiac output, bradycardia, tachyarrhythmias, hyponatremia and ischemia (coronary, mesenteric, skin, digital). (6)To report SUSPECTED ADVERSE REACTIONS, contact Baxter Healthcare at 1-866-888-2472 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch.

ANIMAL PHARMACOLOGY & OR TOXICOLOGY SECTION.

13.2 Animal Toxicology and/or Pharmacology No toxicology studies were conducted with vasopressin.

CARCINOGENESIS & MUTAGENESIS & IMPAIRMENT OF FERTILITY SECTION.

13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility No formal carcinogenicity or fertility studies with vasopressin have been conducted in animals. Vasopressin was found to be negative in the in vitro bacterial mutagenicity (Ames) test and the in vitro Chinese hamster ovary (CHO) cell chromosome aberration test. In mice, vasopressin has been reported to have an effect on function and fertilizing ability of spermatozoa.

CLINICAL PHARMACOLOGY SECTION.

12 CLINICAL PHARMACOLOGY 12.1 Mechanism of Action Vasopressin causes vasoconstriction by binding to V1 receptors on vascular smooth muscle coupled to the Gq/11-phospholipase C-phosphatidyl-inositol-triphosphate pathway, resulting in the release of intracellular calcium. In addition, vasopressin stimulates antidiuresis via stimulation of V2 receptors which are coupled to adenyl cyclase.. 12.2 Pharmacodynamics At therapeutic doses exogenous vasopressin elicits vasoconstrictive effect in most vascular beds including the splanchnic, renal and cutaneous circulation. In addition, vasopressin at pressor doses triggers contractions of smooth muscles in the gastrointestinal tract mediated by muscular V1-receptors and release of prolactin and ACTH via V3 receptors. At lower concentrations typical for the antidiuretic hormone vasopressin inhibits water diuresis via renal V2 receptors. In addition, vasopressin has been demonstrated to cause vasodilation in numerous vascular beds that are mediated by V2, V3, oxytocin and purinergic P2 receptors.In patients with vasodilatory shock vasopressin in therapeutic doses increases systemic vascular resistance and mean arterial blood pressure and reduces the dose requirements for norepinephrine. Vasopressin tends to decrease heart rate and cardiac output. The pressor effect is proportional to the infusion rate of exogenous vasopressin. The pressor effect reaches its peak within 15 minutes. After stopping the infusion the pressor effect fades within 20 minutes. There is no evidence for tachyphylaxis or tolerance to the pressor effect of vasopressin in patients.. 12.3 Pharmacokinetics Vasopressin plasma concentrations increase linearly with increasing infusion rates from 10 to 200 uU/kg/min. Steady state plasma concentrations are achieved after 30 minutes of continuous intravenous infusion.DistributionVasopressin does not appear to bind plasma protein. The volume of distribution is 140 mL/kg.EliminationAt infusion rates used in vasodilatory shock (0.01 to 0.1 units/minute), the clearance of vasopressin is to 25 mL/min/kg in patients with vasodilatory shock. The apparent t1/2 of vasopressin at these levels is <=10 minutes.MetabolismSerine protease, carboxipeptidase and disulfide oxido-reductase cleave vasopressin at sites relevant for the pharmacological activity of the hormone. Thus, the generated metabolites are not expected to retain important pharmacological activity.ExcretionVasopressin is predominantly metabolized and only about 6% of the dose is excreted unchanged into urine.Specific Populations Pregnancy: Because of spillover into blood of placental vasopressinase, the clearance of exogenous and endogenous vasopressin increases gradually over the course of pregnancy. During the first trimester of pregnancy, the clearance is only slightly increased. However, by the third trimester the clearance of vasopressin is increased about 4-fold and at term up to 5-fold. After delivery, the clearance of vasopressin returns to pre-conception baseline within two weeks.Drug Interaction Studies Indomethacin more than doubles the time to offset for vasopressins effect on peripheral vascular resistance and cardiac output in healthy subjects [see Drug Interactions (7.2)]. The ganglionic blocking agent tetra-ethylammonium increases the pressor effect of vasopressin by 20% in healthy subjects [see Drug Interactions (7.3)]. Halothane, morphine, fentanyl, alfentanyl and sufentanyl do not impact exposure to endogenous vasopressin.. Pregnancy: Because of spillover into blood of placental vasopressinase, the clearance of exogenous and endogenous vasopressin increases gradually over the course of pregnancy. During the first trimester of pregnancy, the clearance is only slightly increased. However, by the third trimester the clearance of vasopressin is increased about 4-fold and at term up to 5-fold. After delivery, the clearance of vasopressin returns to pre-conception baseline within two weeks.. Indomethacin more than doubles the time to offset for vasopressins effect on peripheral vascular resistance and cardiac output in healthy subjects [see Drug Interactions (7.2)]. The ganglionic blocking agent tetra-ethylammonium increases the pressor effect of vasopressin by 20% in healthy subjects [see Drug Interactions (7.3)].. Halothane, morphine, fentanyl, alfentanyl and sufentanyl do not impact exposure to endogenous vasopressin.

CLINICAL STUDIES SECTION.

14 CLINICAL STUDIES Increases in systolic and mean blood pressure following administration of vasopressin were observed in studies in septic shock and in post-cardiotomy vasodilatory shock.

CONTRAINDICATIONS SECTION.

4 CONTRAINDICATIONS Vasopressin in Sodium Chloride Injection is contraindicated in patients with known allergy or hypersensitivity to 8-L-arginine vasopressin.. oVasopressin in Sodium Chloride Injection is contraindicated in patients with known allergy or hypersensitivity to 8-L-arginine vasopressin. (4). oVasopressin in Sodium Chloride Injection is contraindicated in patients with known allergy or hypersensitivity to 8-L-arginine vasopressin. (4).

DESCRIPTION SECTION.

11 DESCRIPTION Vasopressin in Sodium Chloride Injection contains vasopressin, polypeptide hormone. The chemical name of vasopressin is Cyclo (1-6) L-Cysteinyl-L-Tyrosyl-L-Phenylalanyl-L-Glutaminyl-L-Asparaginyl-L-Cysteinyl-L-Prolyl-L-Arginyl-L-Glycinamide. It is white to off-white amorphous powder, freely soluble in water. The structural formula is:Molecular Formula: C46H65N15O12S2 Molecular Weight: 1084.23Vasopressin in Sodium Chloride Injection is sterile, aqueous solution of synthetic arginine vasopressin for intravenous administration. Each 100 mL contains 20 units (0.2 units/mL) or 40 units (0.4 units/mL) of vasopressin. Each 100mL also contains 900 mg Sodium Chloride, 33.6 mg Sodium DL-Lactate, and Water for Injection. pH may have been adjusted with sodium hydroxide and/or hydrochloric acid. It has pH of 3.6 4.0.. Vasopressin Structural Formula.

DOSAGE & ADMINISTRATION SECTION.

2 DOSAGE AND ADMINISTRATION oPost-cardiotomy shock: 0.03 units/minute to 0.1 units/minute by intravenous infusion. (2.1)oSeptic shock: 0.01 units/minute to 0.07 units/minute by intravenous infusion. (2.1). oPost-cardiotomy shock: 0.03 units/minute to 0.1 units/minute by intravenous infusion. (2.1). oSeptic shock: 0.01 units/minute to 0.07 units/minute by intravenous infusion. (2.1). 2.1 Administration This product does not require dilution prior to administration.In general, titrate to the lowest dose compatible with clinically acceptable response.The recommended starting dose is:Post-cardiotomy shock: 0.03 units/minute by intravenous infusionSeptic Shock: 0.01 units/minute by intravenous infusionTitrate up by 0.005 units/minute at 10- to 15-minute intervals until the target blood pressure is reached. There are limited data for doses above 0.1 units/minute for post-cardiotomy shock and 0.07 units/minute for septic shock. Adverse reactions are expected to increase with higher doses.After target blood pressure has been maintained for hours without the use of catecholamines, taper vasopressin injection by 0.005 units/minute every hour as tolerated to maintain target blood pressure.Inspect visually for any particulate matter and discoloration prior to administration. Discard Unused PortionDo not add supplemental medication or additive.

DOSAGE FORMS & STRENGTHS SECTION.

3 DOSAGE FORMS AND STRENGTHS Injection: clear, practically colorless solution for intravenous infusion, supplied in 100-mL single dose ready-to-use containers as:o20 units vasopressin (0.2 units/mL) in 0.9% sodium chloride o40 units vasopressin (0.4 units/mL) in 0.9% sodium chloride. o20 units vasopressin (0.2 units/mL) in 0.9% sodium chloride o40 units vasopressin (0.4 units/mL) in 0.9% sodium chloride. Injection: 100-mL single dose, ready-to-use containers with (3)o20 units vasopressin (0.2 units/mL) in 0.9% sodium chloride.o40 units vasopressin (0.4 units/mL) in 0.9% sodium chloride.. o20 units vasopressin (0.2 units/mL) in 0.9% sodium chloride.. o40 units vasopressin (0.4 units/mL) in 0.9% sodium chloride.

DRUG INTERACTIONS SECTION.

7 DRUG INTERACTIONS oPressor effects of catecholamines and Vasopressin in Sodium Chloride Injection are expected to be additive. (7.1)oIndomethacin may prolong effects of Vasopressin in Sodium Chloride Injection. (7.2)oCo-administration of ganglionic blockers or drugs causing SIADH (syndrome of inappropriate antiduretic hormone secretion) may increase the pressor response. (7.3, 7.4)oCo-administration of drugs causing diabetes insipidus may decrease the pressor response. (7.5) oPressor effects of catecholamines and Vasopressin in Sodium Chloride Injection are expected to be additive. (7.1). oIndomethacin may prolong effects of Vasopressin in Sodium Chloride Injection. (7.2). oCo-administration of ganglionic blockers or drugs causing SIADH (syndrome of inappropriate antiduretic hormone secretion) may increase the pressor response. (7.3, 7.4). oCo-administration of drugs causing diabetes insipidus may decrease the pressor response. (7.5) 7.1 Catecholamines Use with catecholamines is expected to result in an additive effect on mean arterial blood pressure and other hemodynamic parameters. Hemodynamic monitoring is recommended; adjust the dose of vasopressin as needed.. 7.2 Indomethacin Use with indomethacin may prolong the effect of Vasopressin in Sodium Chloride Injection on cardiac index and systemic vascular resistance. Hemodynamic monitoring is recommended; adjust the dose of vasopressin as needed [see Clinical Pharmacology (12.3)] . 7.3 Ganglionic Blocking Agents Use with ganglionic blocking agents may increase the effect of Vasopressin in Sodium Chloride Injection on mean arterial blood pressure. Hemodynamic monitoring is recommended; adjust the dose of vasopressin as needed see Clinical Pharmacology (12.3)].. 7.4 Drugs Suspected of Causing SIADH Use with drugs suspected of causing SIADH (e.g., SSRIs, tricyclic antidepressants, haloperidol, chlorpropamide, enalapril, methyldopa, pentamidine, vincristine, cyclophosphamide, ifosfamide, felbamate) may increase the pressor effect in addition to the antidiuretic effect of Vasopressin in Sodium Chloride Injection. Hemodynamic monitoring is recommended; adjust the dose of vasopressin as needed.. 7.5 Drugs Suspected of Causing Diabetes Insipidus Use with drugs suspected of causing diabetes insipidus (e.g., demeclocycline, lithium, foscarnet, clozapine) may decrease the pressor effect in addition to the antidiuretic effect of Vasopressin in Sodium Chloride Injection. Hemodynamic monitoring is recommended; adjust the dose of vasopressin as needed.

GERIATRIC USE SECTION.

8.5 Geriatric Use Clinical studies of vasopressin did not include sufficient numbers of subjects aged 65 and over to determine whether they respond differently from younger subjects. Other reported clinical experience has not identified differences in responses between the elderly and younger patients. In general, dose selection for an elderly patient should be cautious, usually starting at the low end of the dosing range, reflecting the greater frequency of decreased hepatic, renal, or cardiac function, and of concomitant disease or other drug therapy [see Warnings and Precautions (5), Adverse Reactions (6), and Clinical Pharmacology (12.3)].

HOW SUPPLIED SECTION.

16 HOW SUPPLIED/STORAGE AND HANDLING Vasopressin in Sodium Chloride Injection is supplied as clear, practically colorless solution for intravenous administration in single-dose 100 mL ready-to-use containers available as:Product CodeProduct DescriptionNDC Number2G349820 units vasopressin (0.2 units/mL)Supplied as 12 bags per carton0338-9640-122G349940 units vasopressin (0.4 units/mL)Supplied as 12 bags per carton0338-9647-12Store in the refrigerator (2C to 8C [36F to 46F]). Protect from freezing.If needed, Vasopressin in Sodium Chloride Injection may be stored at room temperature up to 25C (77F) for up to months. Discard after months if stored at room temperature or until the expiration date printed on the carton and container label, whichever is earlier. Once stored at room temperature, do not place back in the refrigerator.The drug product must be stored in its light protective carton during storage.Manufactured by, Packed by, Distributed by:Baxter Healthcare CorporationDeerfield, IL 60015 USAPrinted in USA07-19-06-884Baxter and Galaxy are trademarks of Baxter International Inc.

INDICATIONS & USAGE SECTION.

1 INDICATIONS AND USAGE Vasopressin in Sodium Chloride Injection is indicated to increase blood pressure in adults with vasodilatory shock who remain hypotensive despite fluids and catecholamines.. Vasopressin in Sodium Chloride Injection is indicated to increase blood pressure in adults with vasodilatory shock who remain hypotensive despite fluids and catecholamines. (1).

LACTATION SECTION.

8.2 Lactation There are no data on the presence of vasopressin injection in either human or animal milk, the effects on the breastfed infant, or the effects on milk production.

MECHANISM OF ACTION SECTION.

12.1 Mechanism of Action Vasopressin causes vasoconstriction by binding to V1 receptors on vascular smooth muscle coupled to the Gq/11-phospholipase C-phosphatidyl-inositol-triphosphate pathway, resulting in the release of intracellular calcium. In addition, vasopressin stimulates antidiuresis via stimulation of V2 receptors which are coupled to adenyl cyclase.

NONCLINICAL TOXICOLOGY SECTION.

13 NONCLINICAL TOXICOLOGY 13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility No formal carcinogenicity or fertility studies with vasopressin have been conducted in animals. Vasopressin was found to be negative in the in vitro bacterial mutagenicity (Ames) test and the in vitro Chinese hamster ovary (CHO) cell chromosome aberration test. In mice, vasopressin has been reported to have an effect on function and fertilizing ability of spermatozoa.. 13.2 Animal Toxicology and/or Pharmacology No toxicology studies were conducted with vasopressin.

OVERDOSAGE SECTION.

10 OVERDOSAGE Overdosage with Vasopressin in Sodium Chloride Injection can be expected to manifest as consequences of vasoconstriction of various vascular beds (peripheral, mesenteric, and coronary) and as hyponatremia. In addition, overdosage may lead less commonly to ventricular tachyarrhythmias (including Torsade de Pointes), rhabdomyolysis, and non-specific gastrointestinal symptoms.Direct effects will resolve within minutes of withdrawal of treatment.

PACKAGE LABEL.PRINCIPAL DISPLAY PANEL.

PACKAGE/LABEL PRINCIPAL DISPLAY PANEL Container LabelNDC 0338-9640-12Vasopressinin 0.9% Sodium Chloride Injection20 units per 100 mL(0.2 units/mL)For Intravenous Infusion Only100 mL Single-Dose ContainerDiscard Unused PortionRx onlySterileEach mL of the 0.2 units/mL strength also contains9 mg sodium chloride, 0.336 mg sodium DL-lactate,and water for injection. pH may have been adjustedwith sodium hydroxide or hydrochloric acid.Dosage: See prescribing information.Store refrigerated (2C to 8C [36F to 46F]).If needed, product may be stored at roomtemperature up to 25C (77F) for up to months.Discard after months if stored at roomtemperature.Protect from light. Protect from freezing.Do not add supplemental medication or additives.Code 2G3498BaxterLogoBaxter Healthcare Corporation, Deerfield, IL 60015 USAProduct of USA07-34-00-2342BAR CODE303389640127Container LabelNDC 0338-9647-12Vasopressinin 0.9% Sodium Chloride Injection40 units per 100 mL(0.4 units/mL)For Intravenous Infusion Only100 mL Single-Dose ContainerDiscard Unused PortionRx onlySterileEach mL of the 0.4 units/mL strength also contains9 mg sodium chloride, 0.336 mg sodium DL-lactate,and water for injection. pH may have been adjustedwith sodium hydroxide or hydrochloric acid.Dosage: See prescribing information.Store refrigerated (2C to 8C [36F to 46F]).If needed, product may be stored at roomtemperature up to 25C (77F) for up to months.Discard after months if stored at roomtemperature.Protect from light. Protect from freezing.Do not add supplemental medication or additives.Code 2G3499Baxter LogoBaxter Healthcare Corporation, Deerfield, IL 60015 USAProduct of USA07-34-00-2343BAR CODE303389647126Carton LabelVasopressinin 0.9% Sodium Chloride Injection20 units per 100 mL(0.2 units/mL)Vasopressinin 0.9% Sodium Chloride Injection20 units per 100 mL(0.2 units/mL)NDC 0338-9640-12Vasopressinin 0.9% Sodium Chloride Injection20 units per 100 mL(0.2 units/mL)UNVARNISHED AREA FOR ON-LINEPRINTING OF LOT EXPBar Code303389640127For Intravenous Infusion onlyEach mL of the 0.2 units/mL strength also contains mg sodium chloride, 0.336 mg sodium DL-lactate, and water for injection. pH may have been adjusted with sodium hydroxide or hydrochloric acid.Dosage: See prescribing information.Do not add supplemental medication or additives.Rx only Store refrigerated (2C to 8C [36F to 46F]).If needed, product may be stored at room temperature up to 25C (77F) for up to months.Discard after months if stored at room temperature. The drug product must be stored in its light protective carton during storage.Protect from freezing. Baxter Healthcare CorporationDeerfield, IL 60015 USA07-01-00-1916Vasopressinin 0.9% Sodium Chloride Injection20 units per 100 mL(0.2 units/mL)Vasopressinin 0.9% Sodium Chloride Injection20 units per 100 mL(0.2 units/mL)NDC 0338-9640-12Vasopressinin 0.9% Sodium Chloride Injection20 units per 100 mL(0.2 units/mL)For Intravenous Infusion Only The drug product must be stored in its lightprotective carton during storage. Protect fromfreezing. Code 2G3498Rx only Single-Dose bagDiscard unused portionBaxter logoCarton LabelVasopressinin 0.9% Sodium Chloride Injection40 units per 100 mL(0.4 units/mL)Vasopressinin 0.9% Sodium Chloride Injection40 units per 100 mL(0.4 units/mL)NDC 0338-9647-12Vasopressinin 0.9% Sodium Chloride Injection40 units per 100 mL(0.4 units/mL)UNVARNISHED AREA FOR ON-LINEPRINTING OF LOT EXPBar Code303389647126For Intravenous Infusion onlyEach mL of the 0.4 units/mL strength also contains mg sodium chloride, 0.336 mg sodium DL-lactate, and water for injection. pH may have been adjusted with sodium hydroxide or hydrochloric acid.Dosage: See prescribing information.Do not add supplemental medication or additives.Rx only Store refrigerated (2C to 8C [36F to 46F]).If needed, product may be stored at room temperature up to 25C (77F) for up to months.Discard after months if stored at room temperature. The drug product must be stored in its light protective carton during storage.Protect from freezing. Baxter Healthcare CorporationDeerfield, IL 60015 USA07-01-00-1917Vasopressinin 0.9% Sodium Chloride Injection40 units per 100 mL(0.4 units/mL)Vasopressinin 0.9% Sodium Chloride Injection40 units per 100 mL(0.4 units/mL)NDC 0338-9647-12Vasopressinin 0.9% Sodium Chloride Injection40 units per 100 mL(0.4 units/mL)For Intravenous Infusion Only The drug product must be stored in its lightprotective carton during storage. Protect fromfreezing. Code 2G3499Rx only Single-Dose bagDiscard unused portionBaxter logo. Vasopressin 20 9640-12 Representative Container Label (1 of 2). Vasopressin 20 9640-12 Representative Container Label (2 of 2). Vasopressin 40 9647-12 Representative Container Label (1 of 2). Vasopressin 40 9647-12 Representative Container Label (2 of 2). Vasopressin 20 9640-12 Representative Carton Label (1 of 2). Vasopressin 20 9640-12 Representative Carton Label (2 of 2). Vasopressin 40 9647-12 Representative Carton Label (1 of 2). Vasopressin 40 9647-12 Representative Carton Label (2 of 2).

PEDIATRIC USE SECTION.

8.4 Pediatric Use Safety and effectiveness of Vasopressin in Sodium Chloride Injection in pediatric patients with vasodilatory shock have not been established.

PHARMACODYNAMICS SECTION.

12.2 Pharmacodynamics At therapeutic doses exogenous vasopressin elicits vasoconstrictive effect in most vascular beds including the splanchnic, renal and cutaneous circulation. In addition, vasopressin at pressor doses triggers contractions of smooth muscles in the gastrointestinal tract mediated by muscular V1-receptors and release of prolactin and ACTH via V3 receptors. At lower concentrations typical for the antidiuretic hormone vasopressin inhibits water diuresis via renal V2 receptors. In addition, vasopressin has been demonstrated to cause vasodilation in numerous vascular beds that are mediated by V2, V3, oxytocin and purinergic P2 receptors.In patients with vasodilatory shock vasopressin in therapeutic doses increases systemic vascular resistance and mean arterial blood pressure and reduces the dose requirements for norepinephrine. Vasopressin tends to decrease heart rate and cardiac output. The pressor effect is proportional to the infusion rate of exogenous vasopressin. The pressor effect reaches its peak within 15 minutes. After stopping the infusion the pressor effect fades within 20 minutes. There is no evidence for tachyphylaxis or tolerance to the pressor effect of vasopressin in patients.

PHARMACOKINETICS SECTION.

12.3 Pharmacokinetics Vasopressin plasma concentrations increase linearly with increasing infusion rates from 10 to 200 uU/kg/min. Steady state plasma concentrations are achieved after 30 minutes of continuous intravenous infusion.DistributionVasopressin does not appear to bind plasma protein. The volume of distribution is 140 mL/kg.EliminationAt infusion rates used in vasodilatory shock (0.01 to 0.1 units/minute), the clearance of vasopressin is to 25 mL/min/kg in patients with vasodilatory shock. The apparent t1/2 of vasopressin at these levels is <=10 minutes.MetabolismSerine protease, carboxipeptidase and disulfide oxido-reductase cleave vasopressin at sites relevant for the pharmacological activity of the hormone. Thus, the generated metabolites are not expected to retain important pharmacological activity.ExcretionVasopressin is predominantly metabolized and only about 6% of the dose is excreted unchanged into urine.Specific Populations Pregnancy: Because of spillover into blood of placental vasopressinase, the clearance of exogenous and endogenous vasopressin increases gradually over the course of pregnancy. During the first trimester of pregnancy, the clearance is only slightly increased. However, by the third trimester the clearance of vasopressin is increased about 4-fold and at term up to 5-fold. After delivery, the clearance of vasopressin returns to pre-conception baseline within two weeks.Drug Interaction Studies Indomethacin more than doubles the time to offset for vasopressins effect on peripheral vascular resistance and cardiac output in healthy subjects [see Drug Interactions (7.2)]. The ganglionic blocking agent tetra-ethylammonium increases the pressor effect of vasopressin by 20% in healthy subjects [see Drug Interactions (7.3)]. Halothane, morphine, fentanyl, alfentanyl and sufentanyl do not impact exposure to endogenous vasopressin.. Pregnancy: Because of spillover into blood of placental vasopressinase, the clearance of exogenous and endogenous vasopressin increases gradually over the course of pregnancy. During the first trimester of pregnancy, the clearance is only slightly increased. However, by the third trimester the clearance of vasopressin is increased about 4-fold and at term up to 5-fold. After delivery, the clearance of vasopressin returns to pre-conception baseline within two weeks.. Indomethacin more than doubles the time to offset for vasopressins effect on peripheral vascular resistance and cardiac output in healthy subjects [see Drug Interactions (7.2)]. The ganglionic blocking agent tetra-ethylammonium increases the pressor effect of vasopressin by 20% in healthy subjects [see Drug Interactions (7.3)].. Halothane, morphine, fentanyl, alfentanyl and sufentanyl do not impact exposure to endogenous vasopressin.

PREGNANCY SECTION.

8.1 Pregnancy Risk SummaryThere are no available data on Vasopressin in Sodium Chloride Injection use in pregnant women to inform drug associated risk of major birth defects, miscarriage, or adverse maternal or fetal outcomes. Animal reproduction studies have not been conducted.Clinical Considerations Dose Adjustments During Pregnancy and the Postpartum Period: Because of increased clearance of vasopressin in the second and third trimester, the dose of Vasopressin in Sodium Chloride Injection may need to be increased [see Dosage and Administration (2.1) and Clinical Pharmacology (12.3)]. Maternal Adverse Reactions: Vasopressin in Sodium Chloride Injection may produce tonic uterine contractions that could threaten the continuation of pregnancy.. Dose Adjustments During Pregnancy and the Postpartum Period: Because of increased clearance of vasopressin in the second and third trimester, the dose of Vasopressin in Sodium Chloride Injection may need to be increased [see Dosage and Administration (2.1) and Clinical Pharmacology (12.3)].. Maternal Adverse Reactions: Vasopressin in Sodium Chloride Injection may produce tonic uterine contractions that could threaten the continuation of pregnancy.

SPL UNCLASSIFIED SECTION.

2.1 Administration This product does not require dilution prior to administration.In general, titrate to the lowest dose compatible with clinically acceptable response.The recommended starting dose is:Post-cardiotomy shock: 0.03 units/minute by intravenous infusionSeptic Shock: 0.01 units/minute by intravenous infusionTitrate up by 0.005 units/minute at 10- to 15-minute intervals until the target blood pressure is reached. There are limited data for doses above 0.1 units/minute for post-cardiotomy shock and 0.07 units/minute for septic shock. Adverse reactions are expected to increase with higher doses.After target blood pressure has been maintained for hours without the use of catecholamines, taper vasopressin injection by 0.005 units/minute every hour as tolerated to maintain target blood pressure.Inspect visually for any particulate matter and discoloration prior to administration. Discard Unused PortionDo not add supplemental medication or additive.

USE IN SPECIFIC POPULATIONS SECTION.

8 USE IN SPECIFIC POPULATIONS oPregnancy: May induce tonic uterine contractions. (8.1)oPediatric Use: Safety and effectiveness have not been established. (8.4)oGeriatric Use: No safety issues have not been identified in older patients. (8.5). oPregnancy: May induce tonic uterine contractions. (8.1). oPediatric Use: Safety and effectiveness have not been established. (8.4). oGeriatric Use: No safety issues have not been identified in older patients. (8.5). 8.1 Pregnancy Risk SummaryThere are no available data on Vasopressin in Sodium Chloride Injection use in pregnant women to inform drug associated risk of major birth defects, miscarriage, or adverse maternal or fetal outcomes. Animal reproduction studies have not been conducted.Clinical Considerations Dose Adjustments During Pregnancy and the Postpartum Period: Because of increased clearance of vasopressin in the second and third trimester, the dose of Vasopressin in Sodium Chloride Injection may need to be increased [see Dosage and Administration (2.1) and Clinical Pharmacology (12.3)]. Maternal Adverse Reactions: Vasopressin in Sodium Chloride Injection may produce tonic uterine contractions that could threaten the continuation of pregnancy.. Dose Adjustments During Pregnancy and the Postpartum Period: Because of increased clearance of vasopressin in the second and third trimester, the dose of Vasopressin in Sodium Chloride Injection may need to be increased [see Dosage and Administration (2.1) and Clinical Pharmacology (12.3)].. Maternal Adverse Reactions: Vasopressin in Sodium Chloride Injection may produce tonic uterine contractions that could threaten the continuation of pregnancy.. 8.2 Lactation There are no data on the presence of vasopressin injection in either human or animal milk, the effects on the breastfed infant, or the effects on milk production.. 8.4 Pediatric Use Safety and effectiveness of Vasopressin in Sodium Chloride Injection in pediatric patients with vasodilatory shock have not been established.. 8.5 Geriatric Use Clinical studies of vasopressin did not include sufficient numbers of subjects aged 65 and over to determine whether they respond differently from younger subjects. Other reported clinical experience has not identified differences in responses between the elderly and younger patients. In general, dose selection for an elderly patient should be cautious, usually starting at the low end of the dosing range, reflecting the greater frequency of decreased hepatic, renal, or cardiac function, and of concomitant disease or other drug therapy [see Warnings and Precautions (5), Adverse Reactions (6), and Clinical Pharmacology (12.3)].

WARNINGS AND PRECAUTIONS SECTION.

5 WARNINGS AND PRECAUTIONS oCan worsen cardiac function (5.1)oReversible diabetes insipidus (5.2). oCan worsen cardiac function (5.1). oReversible diabetes insipidus (5.2). 5.1 Worsening Cardiac Function A decrease in cardiac index may be observed with the use of vasopressin.. 5.2 Reversible Diabetes Insipidus Patients may experience reversible diabetes insipidus, manifested by the development of polyuria, dilute urine, and hypernatremia, after cessation of treatment with vasopressin. Monitor serum electrolytes, fluid status and urine output after vasopressin discontinuation. Some patients may require readministration of vasopressin or administration of desmopressin to correct fluid and electrolyte shifts.